The stage of cancer at the time of treatment is the most important factor affecting treatment outcome: early diagnosis is associated with more than a 75% 5-year survival rate whereas late diagnosis is associated with less than a 25% 5-year survival. While survival rates for many cancers have improved during the past twenty years, the survival rate for oral cancer has remained unchanged because most cases are diagnosed at advanced stages. The natural history of oral cancer is such that the asymptomatic, pre-malignant lesion can be identified long before malignant transformation if individuals are properly evaluated and adequate assessment technology exists to support the diagnostic process. The unaided clinical examination alone is inadequate for detecting early oral cancer, even when performed by experienced clinicians, and ultimately will require adjuvant assessment tests to improving early detection. As recommended in Objective 9.6 of Healthy People 201 0 earlier detection is essential to improve treatment outcomes for oral cancer. Earlier detection will require technologies that improve visualization of, or surveillance for, early mucosal changes associated with dysplasia or malignancy, combined with diagnostic tests which accurately characterize the malignancy potential. This project will systematically examine selected current and/or emerging technologies to determine their utility and optimal application, alone or in combination, to reliably detect oral cancer / pre-cancer at its earliest stage by applying the tests to low-risk, high-risk and known oral cancer lesions. Unlike previous studies this project will allow every subject and lesion to be exposed to every assessment test, with specific attention to populations with varying risk for oral cancer and to the intended use of a test as a screening, surveillance, adjuvant or definitive diagnostic tool. The inclusion in this study of emerging technologies will facilitate the analytical validation of tests which could revolutionize the detection and diagnosis of oral cancer. It is expected that insights gained from this study will be hypothesis-provoking, leading to new ideas about biomarkers for oral cancer and their exploitation for the prevention, early detection and treatment of oral cancer.